The purpose of these studies is to establish the basic developmental, cellular and molecular events operating in the regulation of the gene sequences coding for fetal gamma and adult beta A and beta C globins synthesized by sheep erythroid cells. The ultimate goal is to provide a biological rational for the therapeutic re-utilization of the human gamma gene in disease conditions where defective beta globin polypeptide synthesis results in severe anemia. In vivo and in vitro, erythropoietin (ESF) causes a switch from beta A to beta C globin synthesis in adult sheep bone marrow cells. The detailed ontogeny of the beta A to beta C switch is sought in terms of 1) which precursor cells in the erythroid developmental series are phenotypically modulatable by ESF, and 2) whether ESF modulation involves regulating differential transcriptional activity within individual cells comprising a hemogeneously pleuripotent population or the selective mitogenesis of precursor sub-populations of cells already committed to predetermined levels of beta A and beta C gene activity. Recent experiments have demonstrated that fetal liver erythroid cells producing only gamma globin is stimulated by ESF to synthesize beta C globin in vitro, but not in vivo. This observation provides the impetus for future experiments to identify microenvironmental or hormone-like factors controlling globin phenotype.